This invention relates to an improved process for preparing acridine derivatives. In particular it relates to the synthesis of compounds which are capable of sensitizing multidrug-resistant cancer cells to chemotherapeutic agents.
The multidrug-resistant inhibitor (MDRI), chemically known as N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]phenyl}-9 ,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide and its physiologically acceptable salts is described in World Patent Application WO 92/12132, filed in the name of Laboratories Glaxo S.A. and published Jul. 23, 1992 and also described in World Patent Application WO 96/11007, filed in the name of Glaxo Wellcome Inc. and published Apr. 18, 1996. The compounds are disclosed as being useful in sensitizing multidrug-resistant cancer cells to chemotherapeutic agents.
In WO 92/12132, an acridine derivative was disclosed as synthesized by reacting compounds in the presence of coupling reagents commonly used in peptide synthesizing. The coupling reagents disclosed included dicyclohexylcarbodiimide (optionally in the presence of 1-hydroxybenzotriazole), diphenylphosphoryl azide or N, N-carbonyidiimidazole. Suitable inert solvents for the reaction included an ether, halogenated hydrocarbons, amides or ketones.
The synthesis of N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]phenyl}-9 ,10-dihydro-5-methoxy-9-oxo4-acridine carboxamide and its physiologically acceptable salts and solvates is also disclosed by Ne'rina Dodic et al., Journal of Medicinal Chemistry, 1995, Vol. 38 No. 13, pages 2418-2426. The synthesis route in Dodic utilized the same coupling reagents as set forth in WO 92/12132. In the Dodic article, example 84 corresponds to N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl}-9, 10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide.